DETAILED ACTION
Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Withdrawal of Finality
Applicant's request for reconsideration of the finality of the rejection of the last Office action is persuasive and, therefore, the finality of that action is withdrawn.
Claim Status
Claims 1-30 and 60 are cancelled. Claims 31-59 and 61-84 as filed on 10 June 2025 are pending. Claims are 59, 61, 66, 73, and 83 withdrawn. Claims 31-58, 62-65, 67-72, 74-82, and 84 are under examination.
Rejections Withdrawn
Objection to claim 75 is withdrawn with applicant amendment to claim.
Rejection of claims 31-58, 62, 64-65, 67-72, 74-80, and 84 under 35 U.S.C. 102(a)(2) is withdrawn with applicant presenting the disqualification of the prior art Thanos (US 12024709 B2) (Of Record) based on common ownership made by applicant in Remarks dated 10 June 2025 page 23 in par 3 and page 24 in par 1 of “Analysis”. Examiner notes that Thanos does have priority to before the application as its claims have support in 62811521 filed 02/27/2019. The common ownership overcomes the 102 art rejection.
Rejection of claims 31, 39, 56, 62-63 and 82 under 35 U.S.C. 103 is withdrawn with applicant statement of common ownership of Thanos.
Rejection of claims 31-58, 62-65, 67-72, 74-82, and 84 under Obvious style double patenting are withdrawn applicant statement of common ownership of Thanos.
New Rejections necessitated by Applicant Amendment. Applicant arguments related to Thanos as prior art in relation to the withdrawn art rejections and Double Patenting Rejections are not responded to.
Rejections Maintained
Claim Rejections - 35 USC § 112
The following is a quotation of 35 U.S.C. 112(d):
(d) REFERENCE IN DEPENDENT FORMS.—Subject to subsection (e), a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
The following is a quotation of pre-AIA 35 U.S.C. 112, fourth paragraph:
Subject to the following paragraph [i.e., the fifth paragraph of pre-AIA 35 U.S.C. 112], a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
Claim 81 is rejected under 35 U.S.C. 112(d) or pre-AIA 35 U.S.C. 112, 4th paragraph, as being of improper dependent form for failing to further limit the subject matter of the claim upon which it depends, or for failing to include all the limitations of the claim upon which it depends. Claim 81 defines the promoter is a viral promoter of those listed. Claim 81 depends from claim 31 which depends from claim 56. Claim 56 limits the promoters to eukaryotic promoters. Claim 81 states “wherein the promoter is a viral promoter”. This does not fall within the limitations of the claims from which it depends as viruses are not eukaryotes. Applicant may cancel the claim(s), amend the claim(s) to place the claim(s) in proper dependent form, rewrite the claim(s) in independent form, or present a sufficient showing that the dependent claim(s) complies with the statutory requirements.
Claim 81 was not examined further on the merits.
Applicant Arguments
Applicant argues a viral promoter in a eukaryotic cell is a eukaryotic promoter. Applicant points to the specification page 21 in lines 26-34 and page 168 in line 20 to page 181 in line 2. Applicant argues that the viral promoters are recognized by RNA polymerase II and are then eukaryotic promoters. Applicant cites Papadakis et. al. in support of this argument.
Response to Arguments
Applicant's arguments filed 10 June 2025 have been fully considered but they are not persuasive.
Examiner points to the teachings of Papadakis attached by Applicant which groups viral promoters separately from eukaryotic promoters (page 89 in col 2 in par 1 and page 91 in col 2 in par 2). Examiner notes Papadakis states “. . . viral promoters are required for efficient viral propagation, and they frequently induce much higher levels of transcription than eukaryotic promoters . . .” in page 89 col 2 in par 1 in lines 3-6. The statements of Papadakis show that the review article is grouping viral promoters separately from eukaryotic promoters.
Examiner notes that the applicant appears to have support in their specification for viral and eukaryotic promoters. But a viral promoter is not a species of eukaryotic promoter.
New Rejections
Claim Rejections - 35 USC § 102
The following is a quotation of the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention.
(a)(2) the claimed invention was described in a patent issued under section 151, or in an application for patent published or deemed published under section 122(b), in which the patent or application, as the case may be, names another inventor and was effectively filed before the effective filing date of the claimed invention.
Claims 56 and 84 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Petit (WO 2015/126921 A1) (OF RECORD).
Regarding claims 56 and 84, Petit teaches a recombinant listeria bacteria that comprises a biomarker for a disease that when administered to a subject acts a therapeutic leading to immunostimulation that treats the disease (abstract). Petit teaches the recombinant protein in the recombinant listeria bacteria is deficient in an AA metabolism enzyme including asnb which is L-asparaginase II (abstract and [0196]). Petit teaches the listeria expresses a biomarker that targets an immunological response to a disease from the subject including the disease cancer ([0215]). Petit teaches the listeria comprises a plasmid and teaches a promoter controlling the plasmid in Figure 6A. Petit teaches the use of other promoters including “tissue-specific” promoters which would be used in humans which would include eukaryotic promoters ([0288]).
New Rejections
Claim Rejections - 35 USC § 103
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
Claims 31-33, 49-50, 56, 58, and 80 are rejected under 35 U.S.C. 103 as being unpatentable over Petit (WO 2015/126921 A1) (OF RECORD), Wood and Paterson. Front Cell Infect Microbio. 4(51):1-22. (2014) (OF RECORD), and Corr and O’Neill. Cellular Microbiology. 11(5):703-709. (2009) (OF RECORD).
Regarding claims 56 and 49, Petit teaches a recombinant listeria bacteria that comprises a biomarker for a disease that when administered to a subject acts a therapeutic leading to immunostimulation that treats the disease (abstract). Petit teaches the recombinant protein in the recombinant listeria bacteria is deficient in an AA metabolism enzyme including asnb which is L-asparaginase II (abstract and [0196]). Petit teaches the listeria expresses a biomarker that targets an immunological response to a disease from the subject including the disease cancer ([0215]). Petit teaches the listeria comprises a plasmid and teaches a promoter controlling the plasmid in Figure 6A. Petit teaches the use of other promoters including “tissue-specific” promoters which would be used in humans which would include eukaryotic promoters ([0288]).
Regarding claims 31 and 50, Petit teaches live attenuated listeria for use in the invention (0423]).
Regarding claim 32, Petit teaches a reducing in T regulatory cells which would increase persistent of T cells (Example 19).
Regarding claim 58, as the bacterium of Petit is taught as administered as a therapeutic it would inherently be in a pharmaceutical composition.
Regarding claim 80, the promoters of Petit are recognized by RNA polymerase II ([0284], [0288]).
Petit does not teach the disruption of TLR2, TLR4, or TLR5 recognition for the attenuated listeria.
This deficiency is filled by Wood and Corr.
Wood teaches attenuated listeria for use in tumor immunotherapy and that the innate immune response to listeria is mediated through TLRs (summary and page 3 in col 2 in par 1).
Corr teaches listeria that evades TLR response due to variation of genes in listeria (summary and Figure 1). Corr teaches the use of listeria as a vaccine vector for treatment of cancer (page 708 in col 1 in lines 4-11).
It would have been obvious at the time the application was filed to combine live attenuated listeria of Petit that delivers an immunotherapeutic with attenuated listeria that is not recognized by TLR as taught by Corr in view of Wood. One of skill in the art would have been motivated to avoid the dominant immune response to the listeria used in Petit to preserve the bacteria so it can be used in its therapeutic application. Wood teaches that TLR is the dominant recognition for the immune response to listeria and Corr provides mutant listeria that would avoid TLR response. The combination or Petit, Wood, and Corr would have been obvious as they are all in art analogous to the claims immunotherapeutic bacterium. There would have been a reasonable expectation of success as Petit, Wood, and Corr teach attenuated listeria for use in immunotherapeutic methods and attenuating listeria is well known in the art.
Regarding claim 33, the claim requires the therapeutic product confers or contributes to an anti-tumor immune response of one of selected. This activity would be inherent biological activity by administering the immunotherapeutic bacterium of Petit in view of Corr and Wood.
Claims 31-38, 44, 47, 49, 51-54, 56, 58, 62-63, and 84 are rejected under 35 U.S.C. 103 as being unpatentable over Petit (WO 2015/126921 A1) (OF RECORD), Kaimala et. al. Frontiers in Oncology. 8(136): 1-9. (2018) (OF RECORD), Kong et. al. Infect Immun. 80(9):33215-3324 (2012) (OF RECORD), and Han et. al. Cytokine. 56:804-810 (2011) (OF RECORD).
The teachings of Petit from the previous art rejections are incorporated here in full.
Petit does not teach the disruption of TLR2, TLR4, or TLR5 recognition for the attenuated listeria as required by claim 31 and does not teach the bacterium comprises cytokines for use in the plasmid or the specific cytokine of IL-15/IL-15R alpha chain complex elected by applicant.
These deficiencies are filled by Kaimala, Kong, and Han.
Kaimala teaches the use of attenuated bacteria as tools in cancer treatment including the use of attenuated Salmonella having an advantage due to its ability to replicate and remain viable in necrotic tissue (abstract). Kaimala teaches the use of recombinant salmonella strains that express the cytokine IL-2 which had superior anti-tumor activity, the same is true with other cytokines expressed by Salmonella strains (page 3 in col 2 in par 1 and page 4 in col 1 in lines 1-9). Kaimala further teaches attenuated Salmonella expressing chemokines had increased cytotoxic activity against target cells (page 4 in col 1 in lines 9-14). Kaimala teaches the use of multiple species of bacteria in this method including listeria and salmonella (page 4 col 2). Kaimala teaches the loss of efficacy of this method with active toll like receptor (TLR) response via MyD88 (page 6 in col 2 in par 1 and page 7 in col 1).
Kong teaches TLR4 response to salmonella occurs through myD88 response but further teaches the msbB, pagL, pagP, lpxR mutant produces an altered Lipid A phosphorylation that resulted in a bacteria that was still able to colonize a mouse when administered with reduced TLR4 response (page 3322 in col 1 in par 1). Kong teaches the use of their mutant strains as advantageous for Salmonella vaccines (page 3324 in col 1).
Han teaches an IL-15:IL-15R alpha superagonist complex as a promising cytokine for use in treatment for cancer and viral disease (abstract). Han teaches significant immunostimulatory response when administered to mice with a half-life of 25 hours when compared to the cytokine IL-15 (abstract). Han teaches a plasmid vector comprising an IRES region and the IL-15:IL-15R alpha superagonist complex (page 3 in par 1) where it could be expressed in cells (page 3 in par 2).
Regarding claim 44, Han teaches the complex comprises and Fc domain (Figure 1).
It would have been obvious at the time the application was filed to substitute the attenuated listeria bacteria used to express a therapeutic protein for treatment of cancer of Petit with the attenuated Salmonella of Kaimala and Kong to produce an attenuated Salmonella with reduced TLR4 stimulation by the subject that produced therapeutic proteins including cytokines. One of skill in the art would have been motivated by the teachings of Kaimala to use the Salmonella as Salmonella shows increased effectiveness in the aerobic conditions of the tumor microenvironment and Kong teaches its superiority over other bacteria hosts for use in immunotherapeutics. One of skill in the art would have been motivated to use the strain that avoids the MyD88-TLR4 immune response of the subject as it is the one downfall of Salmonella pointed to by Kaimala and the strain of Kong completely overcomes this issue. There would have been a reasonable expectation of success as Petit teaches the effectiveness of bacteria in the method of treatment where the bacteria encodes a therapeutic protein and Kaimala and Kong teach the increased effectiveness of Salmonella in general and the strain of Kong specifically.
Regarding the cytokine elected by applicant of IL-15:IL-15R alpha, it would have been obvious at the time the application was filed to substitute the generic cytokine of Kaimala with the IL-15:IL-15R alpha complex of Han for use in the method taught by Petit in view of Kaimala and Kong to produce an attenuated salmonella that produces immunotherapeutic proteins for use in the treatment of cancer. One of skill in the art would have been motivated to use the highly effective cytokine of Han for increased effectiveness in treating cancer. There would have been a reasonable expectation of success as it would have been a simple substitution of cytokines known to work in the method with a proven and more effective cytokine in the same method of treating cancer where the cytokine was shown to work in a plasmid as used by Petit.
Regarding claims 37-38, applicant teaches its elected species would have these biological effects (Example 38 of the specification) showing that by teaching the bacterium of claim 31 the art teaches these outcomes.
Regarding claim 53-54, as the art is teaching the use of Salmonella it would express the Salmonella gene rck as required by claims.
Regarding claim 58, as Petit, Kaimal, and Kong are all teaching the administration to a subject it would inherently be in a pharmaceutical composition.
Claims 31, 45, 48, and 56 are rejected under 35 U.S.C. 103 as being unpatentable over Petit (WO 2015/126921 A1) (OF RECORD), Kaimala et. al. Frontiers in Oncology. 8(136): 1-9. (2018) (OF RECORD), Kong et. al. Infect Immun. 80(9):33215-3324 (2012) (OF RECORD), and Han et. al. Cytokine. 56:804-810 (2011) (OF RECORD) as applied to claims 31-38, 44, 47, 49, 51-52, 56, 58, 62-63, and 84 above, and further in view of Felgner et. al. Oncoimmunology. 7(2):1-12 (2018) (OF RECORD).
The teachings of Petit from the previous rejections are incorporated here in full.
Petit does not teach does not teach the disruption of TLR2, TLR4, or TLR5 recognition for the attenuated listeria as required by claim 31 and does not teach the bacterium comprises cytokines for use in the plasmid or the specific cytokine of IL-15IL-15R alpha complex elected by applicant. Further, Petit does not teach the mutation of Flagella.
These deficiencies are filled by Kaimala, Kong, Han, and Felgner.
The teachings of Kaimala, Kong, and Han from previous art rejections are incorporated here in full.
Felgner teaches engineered Salmonella with mutations that overcome limitations of anti-bacteria immunity in bacteria-mediated tumor therapy. Felgner teaches the genetic variation that changed Lipid A and flagella synthesis (abstract).
Felgner teaches the combination resulted in an increased immune-stimulatory capacity that overcame the efficacy-limiting effects of subject pre-exposure. Felgner teaches their method optimized the immune-stimulatory capacity of the attenuated vector strains (abstract).
Claims 56 and 31 are obvious over Petit, Kaimala, Kong, and Han as previously described:
It would have been obvious at the time the application was filed to substitute the attenuated listeria bacteria used to express a therapeutic protein for treatment of cancer of Petit with the attenuated Salmonella of Kaimala and Kong to produce an attenuated Salmonella with reduced TLR4 stimulation by the subject that produced therapeutic proteins including cytokines. One of skill in the art would have been motivated by the teachings of Kaimala to use the Salmonella as Salmonella shows increased effectiveness in the aerobic conditions of the tumor microenvironment and Kong teaches its superiority over other bacteria hosts for use in immunotherapeutics. One of skill in the art would have been motivated to use the strain that avoids the MyD88-TLR4 immune response of the subject as it is the one downfall of Salmonella pointed to by Kaimala and the strain of Kong completely overcomes this issue. There would have been a reasonable expectation of success as Petit teaches the effectiveness of bacteria in the method of treatment where the bacteria encodes a therapeutic protein and Kaimala and Kong teach the increased effectiveness of Salmonella in general and the strain of Kong specifically.
It would have been obvious to further alter the bacteria of Petit in view of Kaimala, Kong, and Han to produce a bacteria lacking a flagella as taught by Felgner to produce a Salmonella strain with altered Lipid A and flagella. One of skill in the art would have been motivated to optimize the bacterial strain as Felnger provides to have the improved immune-strategy for the treatment of cancer. There would have been an expectation of success as Kaimala, Kong, and Felgner are all teaching the improvement of Salmonella to evade subject immunity when used as an attenuated vector in immunotherapy.
Claims 31, 43, 45, 48, and 56-57 are rejected under 35 U.S.C. 103 as being unpatentable over Petit (WO 2015/126921 A1) (OF RECORD), Kaimala et. al. Frontiers in Oncology. 8(136): 1-9. (2018) (OF RECORD), Kong et. al. Infect Immun. 80(9):33215-3324 (2012) (OF RECORD), Han et. al. Cytokine. 56:804-810 (2011) (OF RECORD), Felgner et. al. Oncoimmunology. 7(2):1-12 (2018) (OF RECORD), Retallack (WO 2010/132341 A2) (OF RECORD), and Crull. Thesis for Doctoral Natural Sciences. Hanover Medical School. 1-123. (2011) (OF RECORD).
The teachings of Petit from the previous rejections are incorporated here in full.
Petit does not teach does not teach the disruption of TLR2, TLR4, or TLR5 recognition for the attenuated listeria as required by claim 31 and does not teach the bacterium comprises cytokines for use in the plasmid or the specific cytokine of IL-15IL-15R alpha complex elected by applicant. Further. Petit does not teach the use of the auxotrophic selection marker asd as required in claim 43. Petit does not teach the mutation of Flagella, or the suppression of biofilm by csdG mutation or the lack of activation of curli fimbriae.
These deficiencies are filled by Kaimala, Kong, Han, Felgner, Retallack, and Crull.
The teachings of Kaimala, Kong, Han, and Felgner from previous art rejections are incorporated here in full.
Retallack teaches the use of multiple genes for auxotrophic selection including asd and asnB from the Aspartate Family for use in bacteria encoding recombinant proteins (abstract and [062]). Retallack teaches the use of more than one metabolite when using auxotrophic selection (claim 1).
Crull teaches the use of bacteria-mediated tumor therapy (bottom of page 18 onto 19). Crull teaches tumor colonizing bacteria including Salmonella and Listeria bottom of page 19 onto page 20). Crull teaches the response of TLR5 to the presence of flagella in bacteria providing further reason for the removal of flagella in the bacteria for use as a therapeutic (page 28 in par 1). Crull teaches Salmonella forms biofilm which leads to many chronic infections (bottom of page 28 onto page 29). Crull teaches tumor colonization by Salmonella as a previously unstudied but key part of the use of Salmonella in the treatment of cancer (page 31 in par 2). Crull teaches that Salmonella administered to tumors forms biofilm as protection against phagocytosis by host immune cells and this biofilm formation impacts tumor colonization (page 54 in last paragraph). Crull teaches adrA and csgD are regulators of biofilm formation and curli fimbriae production (page 57 in par 1). Crull created mutants in adrA and csgD impacting curli fimbriae production and biofilm formation and leading to intracellular bacteria in the tumors (page 59 in par 1 and Figure 5A and B). This is confirmed in a mouse model of cancer (page 60 in par 1). Crull teaches the series health impacts of biofilm formation in bacteria in patients including risk to the lungs and further teaches improved delivery of therapeutics by bacteria as they are able to move into the tumor environment with impaired biofilm formation and curli fimbriae production (page 63 in par 1-2).
Regarding the requirements of claims 31 and 56, it would have been obvious at the time the application was filed to substitute the attenuated listeria bacteria used to express a therapeutic protein for treatment of cancer of Petit with the attenuated Salmonella of Kaimala and Kong to produce an attenuated Salmonella with reduced TLR4 stimulation by the subject that produced therapeutic proteins including cytokines. One of skill in the art would have been motivated by the teachings of Kaimala to use the Salmonella as Salmonella shows increased effectiveness in the aerobic conditions of the tumor microenvironment and Kong teaches its superiority over other bacteria hosts for use in immunotherapeutics. One of skill in the art would have been motivated to use the strain that avoids the MyD88-TLR4 immune response of the subject as it is the one downfall of Salmonella pointed to by Kaimala and the strain of Kong completely overcomes this issue. There would have been a reasonable expectation of success as Petit teaches the effectiveness of bacteria in the method of treatment where the bacteria encodes a therapeutic protein and Kaimala and Kong teach the increased effectiveness of Salmonella in general and the strain of Kong specifically.
Regarding the lack of flagella, it would have been obvious to further alter the bacteria of Petit in view of Kaimala, Kong, and Han to produce a bacteria lacking a flagella as taught by Felgner to produce a Salmonella strain with altered Lipid A and flagella. One of skill in the art would have been motivated to optimize the bacterial strain as Felnger provides to have the improved immune-strategy for the treatment of cancer. There would have been an expectation of success as Kaimala, Kong, and Felgner are all teaching the improvement of Salmonella to evade subject immunity when used as an attenuated vector in immunotherapy.
Regarding a second metabolite selection required by claim 43, it would have been obvious at the time the application was filed to combine the auxotrophic selection of Petit with the increased selection of using two metabolites as taught by Retallack to increase selection and produce a further purified bacteria sample. One of skill in the art would have been motivated to optimize the selection and remove unwanted bacteria when producing a therapeutic bacteria. There would have been a reasonable expectation of success as Petit and Retallack are both teaching metabolite selection of recombinant bacteria producing pharmaceuticals.
Regarding the mutation of the bacteria to remove curli fimbriae activation and biofilm formation, one of skill in the art would have been motivated to alter the therapeutic bacteria of Petit in view of Kaimala, Kong, Han, and Felgner in view of Crull to remove the unwanted effects of biofilm and curli fimbriae activation. One of skill in the art would have been motivated due to the well-known in the art health impacts of biofilm and the results of Crull showing improved penetration into tumors. Further, Crull teaches the concern of lung health in patients already hospitalized. There would have been a reasonable expectation of success as Crull is teaching the improvement of bacteria for use as a tumor therapeutic delivery system.
Claims 31, 46, and 56 are rejected under 35 U.S.C. 103 as being unpatentable over Petit (WO 2015/126921 A1) (OF RECORD), Kaimala et. al. Frontiers in Oncology. 8(136): 1-9. (2018) (OF RECORD), Kong et. al. Infect Immun. 80(9):33215-3324 (2012) (OF RECORD), and Han et. al. Cytokine. 56:804-810 (2011) (OF RECORD) as applied to claims 31, 45, 48, and 56 above, and further in view of Rosenberg et. al. J Immunother. 25(3):218-225. (2002). (OF RECORD).
The teachings of Petit from the previous rejections are incorporated here in full.
Petit does not teach does not teach the disruption of TLR2, TLR4, or TLR5 recognition for the attenuated listeria as required by claim 31 and does not teach the bacterium comprises cytokines for use in the plasmid or the specific cytokine of IL-15IL-15R alpha complex elected by applicant. Further, Petit does not teach the mutation of purI and msbB genes.
These deficiencies are filled by Kaimala, Kong, Han, and Rosenberg.
Kong teaches TLR4 response to salmonella occurs through myD88 response but further teaches the msbB, pagL, pagP, lpxR mutant produces an altered Lipid A phosphorylation that resulted in a bacteria that was still able to colonize a mouse when administered with reduces TLR4 response (page 3322 in col 1 in par 1).
Rosenberg teaches the mutation of purI and msbB genes to increase the dependency of the bacteria on adenine and decrease stimulation of tumor necrosis factor-α production (abstract). Rosenberg teaches these selective deletions were genetically stable and the modified bacteria selectively grew in transplanted tumors of a mouse model and reduced tumor growth (page 1 in par 2).
As the teachings of Petit, Kaimala, Kong, and Han render claims 31 and 56 obvious they would be obvious in further view of Rosenberg.
Regarding claim 46, it would have been obvious at the time the application was filed to combine the bacteria of Petit in view of Kaimala, Kong, and Han to further comprise the mutations in purI and msbB as taught by Rosenberg. One of skill in the art would have been motivated by the selective growth in tumors that resulted in reduced tumor growth. The reduction in off target impacts would have been desired by one of skill in the art and further Kong also teaches mutation of the msbB gene in their method. There would have been a reasonable expectation of success as Petit, Kong, Kaimala, Han, and Rosenberg are all teaching the development of mutant bacteria for use in the treatment of cancer and all are showing improved therapeutic effects.
Claims 31, 56, and 82 are rejected under 35 U.S.C. 103 as being unpatentable over Petit (WO 2015/126921 A1) (OF RECORD), Kaimala et. al. Frontiers in Oncology. 8(136): 1-9. (2018) (OF RECORD), Kong et. al. Infect Immun. 80(9):33215-3324 (2012) (OF RECORD), and Han et. al. Cytokine. 56:804-810 (2011) (OF RECORD) as applied to claims 31-38, 44, 47, 49, 51-54, 56, 58, 62-63, and 84 above, and further in view of Shi et. al. (Journal of Controlled Release. 222 (130-140) (2016)) (Of Record).
The teachings of Petit from the previous rejections are incorporated here in full.
Petit does not teach does not teach the disruption of TLR2, TLR4, or TLR5 recognition for the attenuated listeria as required by claim 31 and does not teach the bacterium comprises cytokines for use in the plasmid or the specific cytokine of IL-15IL-15R alpha complex elected by applicant. Petit further does not teach the use of a Poly-A tail or IRES region in the plasmid.
These deficiencies are filled by Kaimala, Kong, Han, and Shi.
The teachings of Kaimala, Kong, and Han from the previous rejections are incorporated here in full.
Han teaches an IL-15:IL-15R alpha superagonist complex as a promising cytokine for use in treatment for cancer and viral disease (abstract). Han teaches significant immunostimulatory response when administered to mice with a half-life of 25 hours when compared to the cytokine IL-15 (abstract). Han teaches a plasmid vector comprising an IRES region and the IL-15:IL-15R alpha superagonist complex (page 3 in par 1) where it could be expressed in cells (page 3 in par 2).
Shi teaches the use of prokaryotic-eukaryotic delivery and expression of therapeutic factors in the tumor microenvironment using Salmonella typhimurium for use in safe delivery of a plasmid vector to target tissues (abstract). Shi further teaches the use in cancer (abstract). Shi teaches plasmids comprising a foreign gene, an IRES element and a poly-A tail (page 136 in col 2 in last 4 lines and Figures 1 and 2).
As previously described claims 31 and 56 are obvious over Petit in view of Kaimala, Kong, and Han producing a bacteria that comprises a plasmid encoding a therapeutic protein of IL-15:IL-15R alpha superagonist complex that comprises an IRES region it would have been obvious at the time the application was filed for the plasmid of Petit in view of Kaimala, Kong, and Han to further comprise the Poly-A tail of Shi. One of skill in the art would have been motivated to stabilize the sequence within the plasmid, Shi provides a known in the art domain of a poly-A tail that can be used in tumor therapeutics. There would have been a reasonable expectation of success as the methods of gene insertion with plasmids was a well-known in the art technique.
New Rejections
Double Patenting
The nonstatutory double patenting rejection is based on a judicially created doctrine grounded in public policy (a policy reflected in the statute) so as to prevent the unjustified or improper timewise extension of the “right to exclude” granted by a patent and to prevent possible harassment by multiple assignees. A nonstatutory double patenting rejection is appropriate where the conflicting claims are not identical, but at least one examined application claim is not patentably distinct from the reference claim(s) because the examined application claim is either anticipated by, or would have been obvious over, the reference claim(s). See, e.g., In re Berg, 140 F.3d 1428, 46 USPQ2d 1226 (Fed. Cir. 1998); In re Goodman, 11 F.3d 1046, 29 USPQ2d 2010 (Fed. Cir. 1993); In re Longi, 759 F.2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Van Ornum, 686 F.2d 937, 214 USPQ 761 (CCPA 1982); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); In re Thorington, 418 F.2d 528, 163 USPQ 644 (CCPA 1969).
A timely filed terminal disclaimer in compliance with 37 CFR 1.321(c) or 1.321(d) may be used to overcome an actual or provisional rejection based on nonstatutory double patenting provided the reference application or patent either is shown to be commonly owned with the examined application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. See MPEP § 717.02 for applications subject to examination under the first inventor to file provisions of the AIA as explained in MPEP § 2159. See MPEP § 2146 et seq. for applications not subject to examination under the first inventor to file provisions of the AIA . A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
The filing of a terminal disclaimer by itself is not a complete reply to a nonstatutory double patenting (NSDP) rejection. A complete reply requires that the terminal disclaimer be accompanied by a reply requesting reconsideration of the prior Office action. Even where the NSDP rejection is provisional the reply must be complete. See MPEP § 804, subsection I.B.1. For a reply to a non-final Office action, see 37 CFR 1.111(a). For a reply to final Office action, see 37 CFR 1.113(c). A request for reconsideration while not provided for in 37 CFR 1.113(c) may be filed after final for consideration. See MPEP §§ 706.07(e) and 714.13.
The USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The actual filing date of the application in which the form is filed determines what form (e.g., PTO/SB/25, PTO/SB/26, PTO/AIA /25, or PTO/AIA /26) should be used. A web-based eTerminal Disclaimer may be filled out completely online using web-screens. An eTerminal Disclaimer that meets all requirements is auto-processed and approved immediately upon submission. For more information about eTerminal Disclaimers, refer to www.uspto.gov/patents/apply/applying-online/eterminal-disclaimer.
Claims 31-58, 62-65, 67-72, 74-82, and 84 provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 3-6, 9-12, 14-19, 21-22, 24, 27-34, 38- 44, 46, 48, 52, 56-66 of copending Application No. 17569290 (reference application). Although the claims at issue are not identical, they are not patentably distinct from each other.
The reference application recites mutations to FLG, purI, msdbB, asd, csgD, ansB, (claim 44),
The reference application recites an immunostimulatory protein comprising a human STING protein with a gain of function mutation of R284G and N154S, that is constitutively active with a non-human CTT including applicant’s elected CTT from a Tasmanian devil (claims 1-15, 26, and 43). The reference application recites the immunostimulatory bacterium comprising the modified STING confers anti-tumor immunity in the tumor microenvironment (claim 26). The reference application recites the contribution to anti-tumor immunity in a tumor microenvironment (claim 26). The reference application recites reduced recognition to TLR2, TLR4, and TLR5 (claim 22). The reference application recites the bacterium is salmonella typhimurium (claims 31-32). The reference application recites the amino acid modifications confer constitutive production of type I IFN (claim 43).
Regarding claims 32-36, 42, 44, and 62, the referent application recites the bacterium comprises one or more cytokine, chemokine, a costimulatory protein or receptor (claim 27). The reference application recites IL-2, IL-7, IL-15/IL-15R alpha chain complex, or effects 4-1BB or 4-1BBL among others (claim 28).
Regarding claims 43, 45-48, and 55, the reference application recites a lack of flagella (claim 23). The reference application recites a strain with deletion of pagP, msbB, purI, csgD (claims 24-25).
Regarding claim 58, the reference application recites a delivery vehicle (claim 19) and a pharmaceutical composition (claim 38). The reference application recites the use of an IRES domain and a poly-A tail (claim 65)
Regarding claims 65-69, the reference application recites SEQ ID NO:306 which matches instant SEQ ID NO: 306 and SEQ ID NO: 353 which matches instant SEQ ID NO: 371 (claims 8-11). The reference application recites comprising a human STING protein with a gain of function mutation of R284G and N154S, that is constitutively active with a non-human CTT including applicant’s elected CTT from a Tasmanian devil (claims 1-15, 26, and 43).
Regarding claims 70-78, the reference application recites a human STING with a non-human CTT including applicant’s elected CTT from a Tasmanian devil including applicant’s elected species of instant SEQ ID NO: 371 which matches applicant’s SEQ ID NO: 371 (claims 17-20, 28, and 37-42). The reference application recites the amino acid modifications confer constitutive production of type I IFN (claim 43). The reference application recites a human STING protein with a gain of function mutation of R284G and N154S, that is constitutively active with a non-human CTT including applicant’s elected CTT from a Tasmanian devil (claims 1-15, 26, and 43).
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Conclusion
No Claims allowable.
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/F.E./Examiner, Art Unit 1643
/JULIE WU/Supervisory Patent Examiner, Art Unit 1643